Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients.

PURPOSE: To evaluate safety and preliminary efficacy of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy (RT) in unresectable head and neck cancer patients. Secondary end points were the measurement of h-R3 serum levels and the assessment of the potential mechanisms of antitumor effect on patient biopsies. Anti-idiotypic response to h-R3 was assessed. To predict pharmacologic effect, a mathematical model for antibodies recognizing antigens expressed in tumors and normal tissues was built. PATIENTS AND METHODS: Twenty-four patients with advanced carcinomas of the head and neck received six once-weekly infusions of h-R3 at four dose levels in combination with RT. Pretreatment tumor biopsies were obtained to evaluate epidermal growth factor receptor expression as an enrollment criterion. Second biopsies were taken to evaluate the proliferative activity and angiogenesis in comparison with the pretreatment samples. Patient serum samples were collected to measure h-R3 levels and anti-idiotypic response. RESULTS: The combination of h-R3 and RT was well tolerated. Antibody-related adverse events consisted in infusion reactions. No skin or allergic toxicity appeared. Overall survival significantly increased after the use of the higher antibody doses. Immunohistochemistry studies of tumor specimens before and after treatment revealed that antitumor response correlated with antiproliferative and antiangiogenic effect. One patient developed antibodies to h-R3. The mathematical model predicted that the maximum difference between the area under the curve in tumors and normal tissues is reached when the antibody has intermediate affinity. CONCLUSION: h-R3 is a well-tolerated drug that may enhance radiocurability of unresectable head and neck neoplasms.     

Prognostic value of the immunohistochemical expression of vascular endothelial growth factors in malignant salivary gland neoplasms: a systematic review and meta-analysis

Background The immunohistochemical expression of vascular endothelial growth factor is a prognostic marker in several cancer types. In salivary gland tumors, the association between vascular endothelial growth factor and prognosis remains unclear. The purpose of this study was to perform a systematic review and meta-analysis to assess whether the immunohistochemical expression of vascular endothelial growth factor in patients with salivary gland neoplasms presents prognostic value. Material and Methods Immunohistochemical studies assessing the predictive value of vascular endothelial growth factor in salivary gland neoplasms were systematically reviewed using PubMed, Scopus, Embase, Cochrane Library, and Web of Science databases. It was assessed any survival rates. The fixed-effect model with an adjusted hazard ratio (HR) and 95% confidence intervals (95% CI) as effect measures were performed in the meta-analysis. The Quality in Prognosis Studies (QUIPS) tool was used to assess the quality of the included studies, and the evidence quality was assessed by the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) system. Results The immunohistochemical overexpression of vascular endothelial growth factor in patients with salivary gland neoplasms was associated with shortened survival (HR=5.37, 95% CI: 2.67-10.83, P = 0.00001). In addition, the presence of vascular endothelial growth factor was tightly associated with tumor size, lymph node metastasis, clinical stage, perineural invasion, vascular invasion, poor local control of the disease, and recurrence. Conclusions The immunohistochemical overexpression of vascular endothelial growth factor in patients with salivary gland neoplasms has prognostic value and was associated with decreased survival time. However, more primary well-designed studies are necessary to increase the level of evidence. Key words:Salivary gland neoplasms, salivary glands, head and neck neoplasms, vascular endothelial growth factors, prognosis.     

Laser therapy for recurrent aphthous stomatitis: an overview

Clinical Oral Investigations - To evaluate therapeutic effects of laser therapy on patients with recurrent aphthous stomatitis assessing evidences from previously published systematic reviews. An...     

Dental and skeletal changes in mild to moderate Class II malocclusions treated by either a Twin-block or Xbow appliance followed by full fixed orthodontic treatment

Objective:To compare the short-term skeletal and dental effects of two-phase orthodontic treatment including either a Twin-block or an XBow appliance.Materials and Methods:This was a retrospective clinical trial of 50 consecutive Class II cases treated in a private practice with either a Twin-block (25) or XBow (25) appliance followed by full fixed orthodontic treatment. To factor out growth, an untreated Class II control group (25) was considered.Results:A MANOVA of treatment/observation changes followed by univariate pairwise comparisons showed that the maxilla moved forward less in the treatment groups than in the control group. As for mandibular changes, the corpus length increase was larger in the Twin-block group by 3.9 mm. Dentally, mesial movement of mandibular molars was greater in both treatment groups. Although no distalization of maxillary molars was found in either treatment group, restriction of mesial movement of these teeth was seen in both treatment groups. Both treatment groups demonstrated increased mandibular incisor proclination with larger increases for the XBow group by 3.3°. The Wits value was decreased by 1.6 mm more in the Twin-block group. No sex-related differences were observed.Conclusions:Class II correction using an XBow or Twin-block followed by fixed appliances occurs through a relatively similar combination of dental and skeletal effects. An increase in mandibular incisor inclination for the XBow group and an increased corpus length for the Twin-block group were notable exceptions. No overall treatment length differences were seen.     

Radiolabeling and biological evaluation of DOTA-Ph-Al derivative conjugated to anti-EGFR antibody ior egf/r3 for targeted tumor imaging and therapy

An appropriate bifunctional chelating agent namely DOTA-Ph-Al was developed for the conjugation with biological vectors (anti EGFr antibody). We hereby report the synthesis of p-bromoacetamidobenzyl derivative of DOTA and its conjugation to monoclonal antibody anti-EGFR ior egf/r3. Immunoconjugate was prepared by conjugation of p-bromoacetamidobenzyl derivative of DOTA with ior egf/r3. Modified antibody was purified by size exclusion chromatography. DOTA-Ph-Al-ior egf/r3 exhibited quantitative 99mTc-labeling (>96%) with specific activity 10-20 mCi/mg of protein and 90Y-labeling with specific activity 2-5 mCi/mg. Immunoreactivity was determined by flow cytometry. Receptor ligand assay on murine cell line EAT and human tumor cell line U-87MG showed Kd = 2.87 nM and 4.86 nM respectively. The stability in serum indicated that 99mTc remained bound to antibodies up to 24h and 98% 90Y was associated with the mAb for five days. Biodistribution characteristics of Ab-conjugate radiolabeled to 99mTc and 90Y radionuclide was examined in BALB/c mice grafted with EAT and athymic mice with U-87MG cell line demonstrated high tumor uptake with 5.5 +/- 1.3 and 7.85 +/- 1.2%ID/g at four and 24 h for 99mTc- DOTA-Ph-AI-ior egf/r3 in EAT tumors after post injection respectively. Maximal radiotracer uptake peaked 17.6 +/- 2.5%ID/g in EAT tumor and 12.89 +/- 0.66% ID/g in U-87MG tumor at 48h for 90Y. The drug excreted through renal routes as the activity in the kidneys was 13.42 +/- 0.33%ID/g at 1 h and 4.51 +/- 1.2%ID/g at 4 h for 99mTc- DOTA-Ph-Al-ior egf/r3.     

Molecular and biochemical expression of TLRs in human amniotic membrane: a comparative study of fresh and cryopreserved specimens

Background

To assess the expression of toll-like receptors (TLRs) in human amniotic membrane (AM) specimens and compare this expression with those of AMs undergoing the standard preservation procedure (handling) for ocular surgery.

Methods

Human fresh (n?=?10; five spontaneous and five cesarean) or handled (n?=?5) AMs were analyzed for TLR gene and protein expression. Two pieces were obtained from each specimen, and subjected to molecular or biochemical analysis. Relative real-time PCR and SDS-PAGE were carried out according to standard procedures. The REST–ANOVA coupled analysis was used to compare the molecular and biochemical data.

Results

The fresh membranes expressed all the TLRs (TLR1-10), with different gene expression as detected/evidenced by the Ct values, the intra-fresh group analysis showing that there was a variation of TLR expression whichvaried within the fresh membranes. The handled AMs retained the TLR expression after standard processing and preservation, but with a particular pattern which included a high TLR3/TLR4 and low TLR6 expression, when compared to the fresh membranes. The molecular data were confirmed by Western blot analysis.

Conclusions

AM is routinely used in several ophthalmic surgical procedures, and notwithstanding its preservation procedure, AM is reported to favour wound healing and exert anti-angiogenic, anti-inflammatory, anti-scarring as well as anti-bacterial activities. The presence of TLRs in handled AM would imply that TLRs might be preserved in AMs used in ocular surgery. The findings herein described provide additional data concerning the presence of TLRs in cryopreserved AM, and suggest a possible contribution of AM in ocular surgery, via the innate immune response.     

Nimotuzumab: beyond the EGFR signaling cascade inhibition

One of the most known oncogenes is the epidermal growth factor receptor (EGFR) family. It activates multiple signaling cascades that promote carcinogenesis and immune evasion. Therefore, these molecules have been extensively targeted in cancer immunotherapy. Beyond EGFR signaling cascade inhibition, some of these agents are able to induce T-cell activation, transforming a passive therapy into a vaccine-like effect. Nimotuzumab is an IgG1 humanized monoclonal antibody directed against the extracellular domain of the EGFR blocking the binding to its ligands. It possesses unique pharmacodynamic properties, which allow treating patients for long-term periods and with very low toxicity. Based on its clinical effect, nimotuzumab has been approved in Cuba and abroad for the treatment of different epithelial tumors. Recently, new potential mechanisms of action of nimotuzumab involving the activation of the innate and adaptive immune response have been reported. This review summarizes the main properties of nimotuzumab in comparison with other EGFR-specific monoclonal antibodies, highlighting its capacity to activate an effective immune response. In addition, differential clinical effects of this antibody and ongoing clinical trials to deeply characterize the biomarkers of clinical benefit are shown.